Discovery of N-Substituted (2-Phenylcyclopropyl)methylamines as Functionally Selective Serotonin 2C Receptor Agonists for Potential Use as Antipsychotic Medications

Guiping Zhang; Jianjun Cheng; John D McCorvy; Paul J Lorello; Barbara J Caldarone; Bryan L Roth; Alan P Kozikowski

doi:10.1021/acs.jmedchem.7b00584

Discovery of N-Substituted (2-Phenylcyclopropyl)methylamines as Functionally Selective Serotonin 2C Receptor Agonists for Potential Use as Antipsychotic Medications

J Med Chem. 2017 Jul 27;60(14):6273-6288. doi: 10.1021/acs.jmedchem.7b00584. Epub 2017 Jul 18.

Authors

Guiping Zhang¹, Jianjun Cheng¹, John D McCorvy², Paul J Lorello³, Barbara J Caldarone³, Bryan L Roth², Alan P Kozikowski¹

Affiliations

¹ Drug Discovery Program, Department of Medicinal Chemistry and Pharmacognosy, College of Pharmacy, University of Illinois at Chicago , Chicago, Illinois 60612, United States.
² National Institute of Mental Health Psychoactive Drug Screening Program, Department of Pharmacology, and Division of Chemical Biology and Medicinal Chemistry, University of North Carolina Chapel Hill Medical School , Chapel Hill, North Carolina 27599, United States.
³ Department of Neurology, Brigham and Women's Hospital, and Harvard NeuroDiscovery Center, Harvard Medical School , Boston, Massachusetts 02115, United States.

Abstract

A series of N-substituted (2-phenylcyclopropyl)methylamines were designed and synthesized, with the aim of finding serotonin 2C (5-HT_2C)-selective agonists with a preference for G_q signaling. A number of these compounds exhibit 5-HT_2C selectivity with a preference for G_q-mediated signaling compared with β-arrestin recruitment. Furthermore, the N-methyl compound (+)-15a, which displayed an EC₅₀ of 23 nM in the calcium flux assay while showing no β-arrestin recruitment activity, is the most functionally selective 5-HT_2C agonist reported to date. The N-benzyl compound (+)-19, which showed an EC₅₀ of 24 nM at the 5-HT_2C receptor, is fully selective over the 5-HT_2B receptor. In an amphetamine-induced hyperactivity model, compound (+)-19 showed significant antipsychotic-drug-like activity. These novel compounds shed light on the role of functional selectivity at the 5-HT_2C receptor with respect to antipsychotic activity.

Publication types

Research Support, N.I.H., Extramural

MeSH terms

Animals
Antipsychotic Agents / chemical synthesis
Antipsychotic Agents / chemistry*
Antipsychotic Agents / pharmacology
Benzylamines / chemical synthesis
Benzylamines / chemistry*
Benzylamines / pharmacology
Cyclopropanes / chemical synthesis
Cyclopropanes / chemistry*
Cyclopropanes / pharmacology
HEK293 Cells
Humans
Hyperkinesis / chemically induced
Hyperkinesis / drug therapy
Male
Methylamines / chemical synthesis
Methylamines / chemistry*
Methylamines / pharmacology
Mice, Inbred C57BL
Receptor, Serotonin, 5-HT2B / metabolism
Receptor, Serotonin, 5-HT2C / metabolism*
Serotonin 5-HT2 Receptor Agonists / chemical synthesis
Serotonin 5-HT2 Receptor Agonists / chemistry*
Serotonin 5-HT2 Receptor Agonists / pharmacology
Stereoisomerism
Structure-Activity Relationship
beta-Arrestins / metabolism

Substances

1-(2-(5-fluoro-2-methoxyphenyl)cyclopropyl)-N-(2-methoxybenzyl)methanamine
Antipsychotic Agents
Benzylamines
Cyclopropanes
Methylamines
Receptor, Serotonin, 5-HT2B
Receptor, Serotonin, 5-HT2C
Serotonin 5-HT2 Receptor Agonists
beta-Arrestins

Grants and funding

R01 MH099993/MH/NIMH NIH HHS/United States